Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002420288 | SCV002723549 | uncertain significance | Cardiovascular phenotype | 2024-04-04 | criteria provided, single submitter | clinical testing | The p.G3575D variant (also known as c.10724G>A), located in coding exon 26 of the APOB gene, results from a G to A substitution at nucleotide position 10724. The glycine at codon 3575 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| New York Genome Center | RCV002467843 | SCV002764315 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2021-07-14 | criteria provided, single submitter | clinical testing | The c.10724G>A (p.Gly3575Asp) variant identified in the APOB gene substitutes a moderately conserved Glycine for Aspartic Acid at amino acid3575/4564 (exon 26/29). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.268) and Benign (REVEL; score:0.09) to the function of the canonical transcript. This variant is reported as both Pathogenic and as a Variant of Uncertain Significance in ClinVar (VarID:440519), and to our current knowledge has not been reported in affectedindividuals in the literature. The p.Gly3575 residue is not within a mapped domain of APOB (UniProtKB:P04114). Given the lack of compelling evidence for its pathogenicity, the c.10724G>A (p.Gly3575Asp) variant identified in the APOB gene is reported as a Variant of Uncertain Significance |
| Fulgent Genetics, |
RCV002467843 | SCV002784033 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2021-08-10 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002467843 | SCV004604755 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2022-12-21 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APOB protein function. ClinVar contains an entry for this variant (Variation ID: 440519). This variant has not been reported in the literature in individuals affected with APOB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3575 of the APOB protein (p.Gly3575Asp). |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508909 | SCV000605959 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |